The term “neurodegenerative disease” encompasses a broad spectrum of phenotypically distinct pathological entities that are connected superficially by their incidence within the brain. The correct functioning of neural networks in the brain requires the strict maintenance of electrochemical gradients across cell membranes. These gradients are extremely energy-intensive and account for approximately 20% of the body's total energy budget.
The essential function of the brain is to support electrochemical cell-to-cell communication, which is estimated to consume 47% of the ATP derived from the oxidation of glucose, with very little in the way of alternative energy substrates available. This intensive energetic demand places constraints on fundamental aspects of brain function, making it acutely sensitive to energetic compromise. Metabolic stress places an acute demand on this relatively restricted energy source, and if energy use continues to exceed generation, nervous system function will soon be compromised. Oxidative stress of this nature often precedes neuronal death and is a component of practically every known neurodegenerative condition. Therefore, ability to minimize oxidative stress can prove effective in progression of neurodegenerative disorders.
N-acetylaspartic acid (NAA) is the second most abundant neuronal amino acid derivative in the brain. NAA provides for a clinical index of neuronal metabolic integrity across almost the entire spectrum of neurodegenerative diseases on account of its tight association with neuronal metabolic integrity. Reductions in the neuronal amino acid derivatives of NAA constitute a marker of metabolic integrity across almost the entire neuropathological spectrum, suggesting involvement of NAA in a fundamental aspect of metabolic homeostasis. However, despite over 50 years of research, the function of NAA in the context of neurodegenerative disease remains obscure.
The natural NAA metabolic cycle is tightly compartmentalized. Experimental evidence indicates that NAA function is restricted to a role in fatty acid synthesis during developmental myelination. This function is dependent on the hydrolytic enzyme aspartoacylase (ASPA). ASPA cleaves NAA into aspartate and free acetate. In the brain, ASPA is restricted primarily to white matter producing oligodendrocytes, while synthesis occurs almost exclusively in neurons.
Cleavage of NAA into aspartate and free acetate provides an acetylated moiety that is believed to support fatty acid synthesis during developmental myelination. Prior experiments suggest that mitochondria have a central role in many neurodegenerative diseases. As NAA can is as an acetyl donor in the myelin lipid synthesis pathway in oligodendrocytes, via the catabolic activity of the enzyme ASPA, it can play a role in progression of neurodegenerative diseases.
It is also believed that both fatty acid and ATP synthesis require a steady supply of acetyl coenzyme A (AcCoA). The overwhelming majority of AcCoA available in the brain comes directly from the oxidation of glucose. Thus, during the intensive period of developmental myelination, the cleavage of NAA by ASPA in oligodendrocytes uncouples fatty acid synthesis from ATP generation by way of supplementing AcCoA.
It is further believed that loss of ASPA function results in demyelination and spongiform degeneration, leading to neurodegenerative disorders such as the inherited pediatric leukodystrophy Canavan disease (CD). CD is the only disease with known pathology associated with abnormally elevated levels of NAA in the brain. Other neurodegenerative disorders such as Alzheimer disease (AD) also has been the subject of much research. Despite progress in therapy, Alzheimer, remain as a debilitating disease, and no current therapy treats the basic defect of such condition. Although neurodegenerative diseases are invariably multi-factorial, the identification of a common stress response would be of considerable therapeutic benefit.
The ability to redirect metabolic resources from non-essential functions likely forms the basis of maintaining cellular integrity in the face of pathological stress. If ASPA activity was increased in neurons, a novel energetic supplement could be achieved by cleaving millimolar concentrations of NAA at its source to support ATP synthesis. The state of art at this time has not described the use of NAA as a source for ATP synthesis. Therefore there is a need in the art to explore such alternative cellular source of AcCoA as an alternative source for ATP synthesis cascade.